tbuckley/cabot-search huggingface dataset:
Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation
Authors: Magnus T. Dillon, Jeane Guevara, Kabir Mohammed, Emmanuel C. Patin, Simon A. Smith, Emma Dean, Gemma N. Jones, Sophie E. Willis, Marcella Petrone, Carlos Silva, Khin Thway, Catey Bunce, Ioannis Roxanis, Pablo Nenclares, Anna Wilkins, Martin McLaughlin, Adoracion Jayme-Laiche, Sarah Benafif, Georgios Nintos, Vineet Kwatra, Lorna Grove, David Mansfield, Paula Proszek, Philip Martin, Luiza Moore, Karen E. Swales, Udai Banerji, Mark P. Saunders, James Spicer, Martin D. Forster, Kevin J. Harrington
Journal: Journal of Clinical Investigation (2023)

BACKGROUNDPhase 1 study of ATRinhibition alone or with radiation therapy (PATRIOT) was a first-in-human phase I study of the oral ATR (ataxia telangiectasia and Rad3-related) inhibitor ceralasertib (AZD6738) in advanced solid tumors.METHODSThe primary objective was safety. Secondary objectives included assessment of antitumor responses and pharmacokinetic (PK) and pharmacodynamic (PD) studies. Sixty-seven patients received 20-240 mg ceralasertib BD continuously or intermittently (14 of a 28-day cycle).RESULTSIntermittent dosing was better tolerated than continuous, which was associated with dose-limiting hematological toxicity. The recommended phase 2 dose of ceralasertib was 160 mg twice daily for 2 weeks in a 4-weekly cycle. Modulation of target and increased DNA damage were identified in tumor and surrogate PD. There were 5 (8%) confirmed partial responses (PRs) (40-240 mg BD), 34 (52%) stable disease (SD), including 1 unconfirmed PR, and 27 (41%) progressive disease. Durable responses were seen in tumors with loss of AT-rich interactive domain-containing protein 1A (ARID1A) and DNA damage-response defects. Treatment-modulated tumor and systemic immune markers and responding tumors were more immune inflamed than nonresponding.CONCLUSIONCeralasertib monotherapy was tolerated at 160 mg BD intermittently and associated with antitumor activity.TRIAL REGISTRATIONClinicaltrials.gov: NCT02223923, EudraCT: 2013-003994-84.FUNDINGCancer Research UK, AstraZeneca, UK Department of Health (National Institute for Health Research), Rosetrees Trust, Experimental Cancer Medicine Centre.
Teaming Up With Palliative Care to Improve Perioperative Goals of Care Communication
Authors: Karleen F. Giannitrapani
Journal: JAMA Network Open (2023)

Varun V. Bansal, MBBS; Daniel Kim, BS; Biren Reddy, BA; Hunter D. D. Witmer, MD, MBA; Ankit Dhiman, MBBS, MS; Frederick A. Godley IV, MD, MS, MBA; Cecilia T. Ong, MD; Sandra Clark, MS; Leah Ulrich, BS; Blase Polite, MD; Ardaman Shergill, MD; Monica Malec, MD; Oliver S. Eng, MD; Sandy Tun, MD; Kiran K. Turaga, MD, MPH
Pharmacotherapy for Alcohol Use Disorder
Authors: Melissa McPheeters, Elizabeth A. O’Connor, Sean Riley, Sara M. Kennedy, Christiane Voisin, Kaitlin Kuznacic, Cory P. Coffey, Mark D. Edlund, Georgiy Bobashev, Daniel E. Jonas
Journal: JAMA (2023)

Importance Alcohol use disorder affects more than 28.3 million people in the United States and is associated with increased rates of morbidity and mortality. Objective To compare efficacy and comparative efficacy of therapies for alcohol use disorder. Data Sources PubMed, the Cochrane Library, the Cochrane Central Trials Registry, PsycINFO, CINAHL, and EMBASE were searched from November 2012 to September 9, 2022 Literature was subsequently systematically monitored to identify relevant articles up to August 14, 2023, and the PubMed search was updated on August 14, 2023. Study Selection For efficacy outcomes, randomized clinical trials of at least 12 weeks’ duration were included. For adverse effects, randomized clinical trials and prospective cohort studies that compared drug therapies and reported health outcomes or harms were included. Data Extraction and Synthesis Two reviewers evaluated each study, assessed risk of bias, and graded strength of evidence. Meta-analyses used random-effects models. Numbers needed to treat were calculated for medications with at least moderate strength of evidence for benefit. Main Outcomes and Measures The primary outcome was alcohol consumption. Secondary outcomes were motor vehicle crashes, injuries, quality of life, function, mortality, and harms. Results Data from 118 clinical trials and 20 976 participants were included. The numbers needed to treat to prevent 1 person from returning to any drinking were 11 (95% CI, 1-32) for acamprosate and 18 (95% CI, 4-32) for oral naltrexone at a dose of 50 mg/d. Compared with placebo, oral naltrexone (50 mg/d) was associated with lower rates of return to heavy drinking, with a number needed to treat of 11 (95% CI, 5-41). Injectable naltrexone was associated with fewer drinking days over the 30-day treatment period (weighted mean difference, −4.99 days; 95% CI, −9.49 to −0.49 days) Adverse effects included higher gastrointestinal distress for acamprosate (diarrhea: risk ratio, 1.58; 95% CI, 1.27-1.97) and naltrexone (nausea: risk ratio, 1.73; 95% CI, 1.51-1.98; vomiting: risk ratio, 1.53; 95% CI, 1.23-1.91) compared with placebo. Conclusions and Relevance In conjunction with psychosocial interventions, these findings support the use of oral naltrexone at 50 mg/d and acamprosate as first-line pharmacotherapies for alcohol use disorder.
Enough
Authors: Katelynn M. Smith
Journal: JAMA (2023)

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Review of Diabetic Foot Ulcers
Authors: Michael B. Strauss, Katherine Wilson
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Screening, Referral, Behavioral Counseling, and Preventive Interventions for Oral Health in Children and Adolescents Aged 5 to 17 Years
Authors: Roger Chou, Christina Bougatsos, Jessica Griffin, Shelley S. Selph, Azrah Ahmed, Rongwei Fu, Chad Nix, Eli Schwarz
Journal: JAMA (2023)

Importance Dental caries is common in children and adolescents aged 5 to 17 years and potentially amenable to primary care screening and prevention. Objective To systematically review the evidence on primary care screening and prevention of dental caries in children and adolescents aged 5 to 17 years to inform the US Preventive Services Task Force. Data Sources MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews (to October 3, 2022); surveillance through July 21, 2023. Study Selection Diagnostic accuracy of primary care screening instruments and oral examination; randomized and nonrandomized trials of screening and preventive interventions and systematic reviews of such studies; cohort studies on primary care oral health screening and preventive intervention harms. Data Extraction and Synthesis One investigator abstracted data; a second checked accuracy. Two investigators independently rated study quality. Random-effects meta-analysis was performed for fluoride supplements and xylitol; for other preventive interventions, pooled estimates were used from good-quality systematic reviews. Main Outcomes and Measures Dental caries, morbidity, functional status, quality of life, harms; diagnostic test accuracy. Results Three systematic reviews (total 20 684 participants) and 19 randomized clinical trials, 3 nonrandomized trials, and 1 observational study (total 15 026 participants) were included. No study compared screening vs no screening. When administered by dental professionals or in school settings, fluoride supplements compared with placebo or no intervention were associated with decreased change from baseline in the number of decayed, missing, or filled permanent teeth (DMFT index) or decayed or filled permanent teeth (DFT index) (mean difference, −0.73 [95% CI, −1.30 to −0.19]) at 1.5 to 3 years (6 trials; n = 1395). Fluoride gels were associated with a DMFT- or DFT-prevented fraction of 0.18 (95% CI, 0.09-0.27) at outcomes closest to 3 years (4 trials; n = 1525), fluoride varnish was associated with a DMFT- or DFT-prevented fraction of 0.44 (95% CI, 0.11-0.76) at 1 to 4.5 years (5 trials; n = 3902), and resin-based sealants were associated with decreased risk of carious first molars (odds ratio, 0.21 [95% CI, 0.16-0.28]) at 48 to 54 months (4 trials; n = 440). No trial evaluated primary care counseling or dental referral. Evidence on screening accuracy, silver diamine fluoride, xylitol, and harms was very limited, although serious harms were not reported. Conclusions and Relevance Administration of fluoride supplements, fluoride gels, varnish, and sealants in dental or school settings improved caries outcomes. Research is needed on the effectiveness of oral health preventive interventions in primary care settings and to determine the benefits and harms of screening.
Bempedoic Acid for Primary Prevention of Cardiovascular Events—Reply
Authors: Steven E. Nissen, Stephen J. Nicholls, A. Michael Lincoff
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Screening and Preventive Interventions for Oral Health in Children and Adolescents Aged 5 to 17 Years
Authors: Michael J. Barry, Wanda K. Nicholson, Michael Silverstein, David Chelmow, Tumaini Rucker Coker, Esa M. Davis, Katrina E. Donahue, Carlos Roberto Jaén, Li Li, Gbenga Ogedegbe, Lori Pbert, Goutham Rao, John M. Ruiz, James Stevermer, Joel Tsevat, Sandra Millon Underwood, John B. Wong
Journal: JAMA (2023)

Importance Oral health is fundamental to health and well-being across the lifespan. Oral health conditions affect the daily lives of school-age children and adolescents, leading to loss of more than 51 million school hours every year. Untreated oral health conditions in children can lead to serious infections and affect growth, development, and quality of life. Objective The US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate screening and preventive interventions for oral health conditions in children and adolescents aged 5 to 17 years. Population Asymptomatic children and adolescents aged 5 to 17 years. Evidence Assessment The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for oral health conditions (eg, dental caries) performed by primary care clinicians in asymptomatic children and adolescents aged 5 to 17 years. The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of preventive interventions for oral health conditions (eg, dental caries) performed by primary care clinicians in asymptomatic children and adolescents aged 5 to 17 years. Recommendations The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of routine screening performed by primary care clinicians for oral health conditions, including dental caries, in children and adolescents aged 5 to 17 years. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of preventive interventions performed by primary care clinicians for oral health conditions, including dental caries, in children and adolescents aged 5 to 17 years. (I statement)
A narrow T cell receptor repertoire instructs thymic differentiation of MHC class Ib-restricted CD8+ regulatory T-cells
Authors: Hye-Jung Kim, Hidetoshi Nakagawa, John Y. Choi, Xuchun Che, Andrew Divris, Qingshi Liu, Andrew E. Wight, Hengcheng Zhang, Anis Saad, Zhabiz Solhjou, Christa Deban, Jamil R. Azzi, Harvey Cantor
Journal: Journal of Clinical Investigation (2023)

Although most CD8+ T cells are equipped to kill infected or transformed cells, a subset may regulate immune responses and preserve self-tolerance. Here, we describe a CD8 lineage that is instructed to differentiate into CD8 T regulatory cells (Tregs) by a surprisingly restricted set of T cell receptors (TCRs) that recognize MHC-E (mouse Qa-1) and several dominant self-peptides. Recognition and elimination of pathogenic target cells that express these Qa-1-self-peptide complexes selectively inhibits pathogenic antibody responses without generalized immune suppression. Immunization with synthetic agonist peptides that mobilize CD8 Tregs in vivo efficiently inhibit antigraft antibody responses and markedly prolong heart and kidney organ graft survival. Definition of TCR-dependent differentiation and target recognition by this lineage of CD8 Tregs may open the way to new therapeutic approaches to inhibit pathogenic antibody responses.
COVID-19 Hospitalization in Solid Organ Transplant Recipients on Immunosuppressive Therapy
Authors: Epiphane Kolla, Alain Weill, Mohamad Zaidan, Eleonora De Martin, Sylvie Colin De Verdiere, Laura Semenzato, Mahmoud Zureik, Lamiae Grimaldi
Journal: JAMA Network Open (2023)

Solid organ transplant recipients are at high risk of severe infection with SARS-CoV-2 compared with the general population. However, factors associated with COVID-19-related severity in this population are still insufficiently explored in the literature.
A Call for More Oral Health Research in Primary Care
Authors: Michael S. Reddy, Rena N. D’Souza, Jennifer Webster-Cyriaque
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Low-Value Surgical Procedures in Low- and Middle-Income Countries
Authors: Loai Albarqouni, Eman Abukmail, Majdeddin MohammedAli, Sewar Elejla, Mohamed Abuelazm, Hosam Shaikhkhalil, Thanya Pathirana, Sujeewa Palagama, Emmanuel Effa, Eleanor Ochodo, Eulade Rugengamanzi, Yousef AlSabaa, Ale Ingabire, Francis Riwa, Burhan Goraya, Mina Bakhit, Justin Clark, Morteza Arab-Zozani, Suzanna Alves da Silva, C. S. Pramesh, Verna Vanderpuye, Eddy Lang, Deborah Korenstein, Karen Born, Stephen Tabiri, Adesoji Ademuyiwa, Ashraf Nabhan, Ray Moynihan
Journal: JAMA Network Open (2023)

Importance Overuse of surgical procedures is increasing around the world and harms both individuals and health care systems by using resources that could otherwise be allocated to addressing the underuse of effective health care interventions. In low- and middle-income countries (LMICs), there is some limited country-specific evidence showing that overuse of surgical procedures is increasing, at least for certain procedures. Objectives To assess factors associated with, extent and consequences of, and potential solutions for low-value surgical procedures in LMICs. Evidence Review We searched 4 electronic databases (PubMed, Embase, PsycINFO, and Global Index Medicus) for studies published from database inception until April 27, 2022, with no restrictions on date or language. A combination of MeSH terms and free-text words about the overuse of surgical procedures was used. Studies examining the problem of overuse of surgical procedures in LMICs were included and categorized by major focus: the extent of overuse, associated factors, consequences, and solutions. Findings Of 4276 unique records identified, 133 studies across 63 countries were included, reporting on more than 9.1 million surgical procedures (median per study, 894 [IQR, 97-4259]) and with more than 11.4 million participants (median per study, 989 [IQR, 257-6857]). Fourteen studies (10.5%) were multinational. Of the 119 studies (89.5%) originating from single countries, 69 (58.0%) were from upper-middle–income countries and 30 (25.2%) were from East Asia and the Pacific. Of the 42 studies (31.6%) reporting extent of overuse of surgical procedures, most (36 [85.7%]) reported on unnecessary cesarean delivery, with estimated rates in LMICs ranging from 12% to 81%. Evidence on other surgical procedures was limited and included abdominal and percutaneous cardiovascular surgical procedures. Consequences of low-value surgical procedures included harms and costs, such as an estimated US $3.29 billion annual cost of unnecessary cesarean deliveries in China. Associated factors included private financing, and solutions included social media campaigns and multifaceted interventions such as audits, feedback, and reminders. Conclusions and Relevance This systematic review found growing evidence of overuse of surgical procedures in LMICs, which may generate significant harm and waste of limited resources; the majority of studies reporting overuse were about unnecessary cesarean delivery. Therefore, a better understanding of the problems in other surgical procedures and a robust evaluation of solutions are needed.
PDP1 is a key metabolic gatekeeper and modulator of drug resistance in FLT3-ITD-positive acute myeloid leukemia
Authors: Islam Alshamleh, Nina Kurrle, Philipp Makowka, Raj Bhayadia, Rahul Kumar, Sebastian Süsser, Marcel Seibert, Damian Ludig, Sebastian Wolf, Sebastian E. Koschade, Karoline Stoschek, Johanna Kreitz, Dominik C. Fuhrmann, Rosa Toenges, Marco Notaro, Federico Comoglio, Jan Jacob Schuringa, Tobias Berg, Bernhard Brüne, Daniela S. Krause, Jan-Henning Klusmann, Thomas Oellerich, Frank Schnütgen, Harald Schwalbe, Hubert Serve
Journal: Leukemia (2023)

Abstract High metabolic flexibility is pivotal for the persistence and therapy resistance of acute myeloid leukemia (AML). In 20–30% of AML patients, activating mutations of FLT3, specifically FLT3-ITD, are key therapeutic targets. Here, we investigated the influence of FLT3-ITD on AML metabolism. Nuclear Magnetic Resonance (NMR) profiling showed enhanced reshuffling of pyruvate towards the tricarboxylic acid (TCA) cycle, suggesting an increased activity of the pyruvate dehydrogenase complex (PDC). Consistently, FLT3-ITD-positive cells expressed high levels of PDP1, an activator of the PDC. Combining endogenous tagging of PDP1 with genome-wide CRISPR screens revealed that FLT3-ITD induces PDP1 expression through the RAS signaling axis. PDP1 knockdown resulted in reduced cellular respiration thereby impairing the proliferation of only FLT3-ITD cells. These cells continued to depend on PDP1, even in hypoxic conditions, and unlike FLT3-ITD-negative cells, they exhibited a rapid, PDP1-dependent revival of their respiratory capacity during reoxygenation. Moreover, we show that PDP1 modifies the response to FLT3 inhibition. Upon incubation with the FLT3 tyrosine kinase inhibitor quizartinib (AC220), PDP1 persisted or was upregulated, resulting in a further shift of glucose/pyruvate metabolism towards the TCA cycle. Overexpression of PDP1 enhanced, while PDP1 depletion diminished AC220 resistance in cell lines and peripheral blasts from an AC220-resistant AML patient in vivo. In conclusion, FLT3-ITD assures the expression of PDP1, a pivotal metabolic regulator that enhances oxidative glucose metabolism and drug resistance. Hence, PDP1 emerges as a potentially targetable vulnerability in the management of AML.